Monday, 14 May, 2018

Targeting cancer cells with sugars

Nanomedicine

Nanocarriers binding the mannose receptor. Picture: C Hohmann

Globally, cancer is the second leading cause of death, also because the efficiency of chemotherapeutics is inadequate due to poor delivery to the tumor. NIM scientist Prof Olivia Merkel and her team develop targeted nanocarrier systems to increase the delivery rates of therapeutic formulations and their specific uptake into the target cells.

In the treatment of cancer, there are still several limitations. Especially the delivery of sufficient amounts of active chemotherapeutic drug is difficult. After the conventional intravenous administration, the therapeutic formulation faces some hurdles before reaching the target site. In most cases, the blood circulation time of the active compound is rather short, and a substantial amount of the remaining active drug accumulates in non-target tissues and leads to the known unpleasant and unwanted side-effects in patients. Therefore, the group of Professor Olivia Merkel focuses on the development of stable and targeted nanocarrier formulations and alternative administration routes. One approach is the targeting of specific sugar receptors expressed on several cancer cells, the mannose and mannose-6-phosphate receptors. The new publication in Advanced Healthcare Materials provides a nice overview of the field and presents first results of a new approach tested in the Merkel Lab.

Mannose for cancer-cell specific drug delivery Every human cell has a cell type-specific repertoire of surface receptors to assure the uptake of needed supplies. Due to their high demand in nutrients for rapid proliferation, cancer cells have a very high affinity for carbohydrate molecules compared to normal cells. Several tumor cells express, for example, mannose receptors and mannose-6-phosphate receptors for efficient endocytosis of these sugars, which are used for intracellular energy synthesis. Hence, mannose has high potential as cancer cell-specific ligand for the targeted delivery of (chemo)therapeutic nanocarriers. The ‘lock and key principle’ describes the binding of such functionalized nanocarriers to the tumor cells: the mannose or mannose-6-phosphate receptors on the cell surface present the lock and the mannose ligand on the nanocarrier the matching key. After binding, the whole complex gets endocytosed. This could be visualized as inverse budding: A cell membrane coated vesicle engulfing the area with the ligand-receptor complex buds inwards into the cytosol. “In our own experiments, we could show a significantly increased uptake of mannosylated carriers over non-modified particles,” Merkel explains. “The mannose receptor-mediated endocytosis enables the active uptake of (drug-)loaded nanocarriers specifically bound to tumor cells.”

Immunotherapy and gene-therapeutic approachExpression of mannose receptor on the surface of antigen-presenting cells (APCs) opens another route for tumor therapy. APCs are the immune cells inducing an immune response by activating the respective lymphocytes (‘white blood cells’), cells directly attacking the target and developing the memory cells for a long-lasting defense. On the contrary, the mannose-6-phosphate receptor can also act as tumor suppressor and is discussed in detail as a new target. Nanocarrier formulations for APC-targeting can be loaded with nucleic acids (‘gene-therapy’) coding for specific genes or an RNA-fragment mixture. Upon successful mannose receptor-mediated delivery to the APCs, those tumor antigens will be presented to lymphocytes and induce a rapid, cancer cell-specific immune response. Such immune cell-based therapeutic approach is called immunotherapy. In addition, this activation of the immune system could lead to a long-lasting anticancer response, often described as cancer vaccination and relapse prevention with professional APCs.

Advantages of nanocarriersFunctionalized nanocarriers encapsulating chemotherapeutics provide several advantages over conventional drug preparations. The loading into the carrier improves solubility of several drugs and acts stabilizing and shielding. Therefore, it highly increases the bioavailability due to extended blood circulation times compared to free drug. The active targeting via surface ligands increases the specificity to cancer cells and the local delivery efficiency of active drug, as well as the stimulation APCs for innovative immunotherapy. In addition, such approach could help to overcome the dose-limiting off-target delivery of conventional chemotherapy, while even reducing the amount of administered drug. Besides the capacity for loading with chemotherapeutics, nanocarriers can be (co-)loaded with imaging probes, for instance, facilitating non-invasive localization of tumor tissue and metastases. Formulations co-encapsulating both, therapeutics and diagnostic probes, are also called ‘theragnostics’.